current concepts of neurohormonal activation in heart...

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Current Concepts of NeurohormonalActivation in Heart FailureMediators and Mechanisms

AACN Advanced Critical Care

Volume 19, Number 4, pp.364–385

© 2008, AACN

Christopher S. Lee, RN, MSN, CCRN

Nancy C. Tkacs, RN, PhD

Neurohormonal activation is a commonly

cited array of phenomena in the body’s phys-

iologic response to heart failure. Although

various neurohormones and pharmacologic

agents that moderate their pathophysiologic

effects have been reviewed in the nursing

literature, both the mechanisms of neuro-

hormonal system activation and cellular and

organ system effects have been described

only in brief. Accordingly, this article reviews

mechanisms of neurohormonal activation

and describes cellular and cardiovascular

effects of the (1) sympathetic nervous

system, (2) renin-angiotensin-aldosterone

system, (3) kallikrein-kininogen-kinin system,

(4) vasopressinergic system, (5) natriuretic

peptide systems, and (6) endothelin in the

context of heart failure. This article implicitly

details the physiologic basis for numerous

current and potential future pharmacologic

agents used in the management of heart fail-

ure. It is intended that this article be used as

a reference for advanced clinical nursing

practice, research, and education.

Keywords: cardiac physiology, heart failure,

neurohormonal activation

A B S T R A C T

Neurohormonal Activation in Heart Failure: Mechanisms and Cardiovascular EffectsHeart failure (HF) is a complex syndrome thatcurrently affects more than 5 million Americans.1

The preclinical signs and clinical manifesta-tions of HF are evidence of both ventriculardysfunction and the (initially compensatory)activation of numerous neurohormonal systems.Since original observations of the deleteriouseffects of neurohormones in the pathophysiol-ogy of HF,2 the field has grown in knowledge ofcellular mechanisms and mediators. A sophis-ticated understanding of neurohormonalactivation in HF is essential to contemporaryadvanced practice nursing for 3 importantreasons. First, basic research increasinglyelucidates the mechanisms by which chronicactivation of many neurohormonal systemscauses further cardiovascular dysfunction in HF.Second, hormone assays are now commonly

Christopher S. Lee is Lecturer and Doctoral Candidate,

School of Nursing, University of Pennsylvania, 420 Guardian

Dr, Philadelphia, PA 19104 ([email protected]).

Nancy C. Tkacs is Associate Professor, School of Nursing,

University of Pennsylvania, Philadelphia.

used in the assessment and diagnosis of personswith HF and in applied clinical research. Third,pharmacologic agents currently used in themanagement of HF target specific componentsof neurohormonal systems. Future HF manage-ment strategies will likely focus on specificaspects of neurohormonal systems, includingtargeting intracellular second messengersystems. (See Tables 1–3 for a glossary of keyterms and for details about anatomic structuresand the major mediators of neurohormonalactivation in HF.)

Accordingly, the purpose of this review is todescribe the mechanisms of neurohormonalactivation and to provide a detailed description

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of cellular and cardiovascular effects of thesympathetic nervous system, renin-angiotensin-aldosterone system (RAAS), kallikrein-kininogen-kinin system, vasopressinergicsystem, natriuretic peptide systems, andendothelin in HF. This review will also serve asa critical reference for advanced practice nursesby providing the physiologic basis for currentand future pharmacologic agents used in themanagement of HF.

Part I: Sympathetic NervousSystem ActivationThe most common characteristics of sympa-thetic nervous system activation in the cardio-vascular system are vasoconstriction, positivechronotropism (increased heart rate), andpositive inotropism (increased contractile

force of the ventricle).3 Another importantcharacteristic of sympathetic nervous systemactivation, particularly in the context of HF, ispositive lusitropism (enhanced ventricularrelaxation).4 In response to the ventriculardysfunction of HF, these sympatheticallymediated cardiovascular changes initiallyresult in a functional hemodynamic responsethat helps restore cardiac output.5 Chronicsympathetic nervous system activation, how-ever, increases myocardial oxygen demand,promotes intracellular calcium toxicity, andgives rise to detrimental proliferative effectssuch as chamber hypertrophy,6 expression ofnoncontractile intracellular proteins,7 andfibrosis.8 The sum of sympathetic nervoussystem effects is a major component of HFpathogenesis.

Table 1: Glossary of Key Terms

Autocrine Modulation of a cell by a hormone produced and secreted by that cell

Baroreceptors Sensory neurons with nerve endings within blood vessel walls that detect

changes in distension or pressure

Cardioprotection Delay of cardiac cell death

Chronotropism Refers to rate of depolarization of pacemaker cells. Positive chronotropism

results in higher heart rate and negative chronotropism results in

lower heart rate

Chemoreceptors Sensory neurons that detect small changes in plasma solute concentration,

such as acid or carbon dioxide

Constitutive Occurs at all times and does not require stimulus to induce

Diastolic depolarization Slow and automatic phase of a pacemaker cell’s activation

Downregulation Internalization and degradation of a number of receptors on the

cell membrane

Endocrine Secretion of a hormone into the bloodstream to travel to target tissues

Hydrolysis Splitting a molecule with the addition of water. Hydrolysis of protein

mediators can result in smaller peptides that may or may not have

biologic effects

Hyperpolarization Decrease in the electronic charge of a cell below its normal resting charge

Inotropism Refers to contractile force of cardiac cells—positive inotropism reflects

greater force of contraction, and negative inotropism reflects a

decrease in force of contraction

Lusitropism Refers to rate of ventricular relaxation—positive lusitropism means

enhanced relaxation and improved chamber filling and negative

lusitropism means slower relaxation and impaired filling

Natriuresis Elimination of sodium through excretion in the urine

Paracrine Refers to the release of hormones that act locally

Phosphorylation Chemical addition of a high-energy phosphate group to a target protein

to modulate its activity

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Signaling coordinating autonomic (sympa-thetic and parasympathetic) control of thecardiovascular system involves a negative feed-back loop (Figure 1) including (1) activation ofperipheral or central sensory receptors thatrespond to changes in physiologic conditions,(2) transmission of impulses via afferent nervefibers to the nucleus tractus solitarius and thento the vasomotor center of the medulla oblon-gata, (3) appropriate changes in parasympa-thetic and sympathetic efferent nerve signals,(4) modulated release of neurotransmittersfrom postganglionic nerve fibers to target tis-sues, (5) activation of cell membrane receptors,(6) augmentation or inhibition of intracellularprocesses, and (7) modulation of local or organsystems.9

Mechanisms of Sympathetic NervousSystem StimulationBaroreceptor FunctionTraditionally, arterial underfilling and the subsequent unloading of arterial, or high-pressure, baroreceptors has been described asthe dominant trigger for sympathetic activation

in HF.10 Arterial baroreceptors are part of afeedback mechanism that also includes inputfrom cardiac chamber and pulmonary venousbaroreceptors (cardiopulmonary baroreceptors)10

and chemoreceptors that exist throughout thebody.11 Collectively, these receptors and theirassociated reflexes regulate hemodynamic andphysiologic homeostasis. Arterial baroreceptorsare nerve endings within the arterial walls of thecarotid sinus, aortic arch, and in renal afferentarterioles12 that rapidly respond to changes in arterial pressure.13 Aortic arch baroreceptorafferent fibers project to the brain via the vagusnerve.14 Carotid sinus baroreceptor afferentfibers project to the brain via Hering’s nerve andthen the glossopharyngeal nerve.14

When arterial blood pressure increases, thebaroreceptor firing rate increases proportion-ately. The increased baroreceptor firing rate istransmitted through the vagi and glossopharyn-geal nerves to the nucleus tractus solitarius.12

Second-order neurons then both inhibit the cardiac accelerator and vasoconstrictor centersand stimulate the vagal parasympathetic center(cardiac deceleration center).12 In combination,

Table 2: Anatomic Structure and Function

Anatomic Structure Primary Function in Context of Heart Failure

Neurological structures

Medulla oblongata Lower portion of the brain stem that controls autonomic function

Nucleus tractus solitarius Portion of the brain stem that receives and carries sensory input

from internal organs and visceral receptors, including

baroreceptors and chemoreceptors

Paraventricular nucleus Area of the hypothalamus that produces arginine vasopressin

Posterior pituitary Gland that contains terminals of neurons projecting from the

supraoptic and paraventricular nuclei and secretes hormones

vasopressin and oxytocin into the circulation

Subfornical organ Area near the fornix that senses changes in osmotic pressure

Supraoptic nucleus Area of the hypothalamus that produces arginine vasopressin

Renal/adrenal structures

Juxtaglomerular cells Cells of the renal afferent arterioles that secrete renin

Macula densa cells Cells of the ascending limb of the loop of Henle that are coupled

with juxtaglomerular cells through mesangial cells

Mesangial cells Cells between the juxtaglomerular and macula densa cells that

allow for chemical coupling

Principal cells Cells of the collecting duct that mediate sodium reabsorption

Zona glomerulosa cells Cells of the adrenal cortex that synthesize, store, and

secrete aldosterone

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Table 3: Major Mediators of Neurohormonal Activation in Heart Failure

Mediator Predominant Effect

Adenylyl cyclase Enzyme that converts adenosine triphosphate (ATP) into the

active second messenger cyclic adenosine monophosphate (cAMP)

Aldosterone Steroid hormone that binds with receptors in principal cells of the late

distal tubule and promotes sodium retention and potassium excretion

Angiotensin converting Enzyme that cleaves angiotensin I to angiotensin II, and it also cleaves

enzyme (kininase II) bradykinin into its metabolites

Angiotensin II Mediator that acts on angiotensin II receptors to cause vasoconstriction

and sodium and water retention in the kidneys

Angiotensinogen Precursor protein that is cleaved by renin to form angiotensin I

Angiotensin I Protein cleaved by angiotensin-converting enzyme to form angiotensin II

Arginine vasopressin Posterior pituitary hormone that acts on vasopressin receptors to

promote vasoconstriction and water conservation

Atrial natriuretic peptide Hormone of cardiac origin that acts on natriuretic peptide receptors

on vascular smooth muscle cells to promote vasodilatation and

on renal cells to eliminate sodium and water

Big endothelin Precursor protein that is cleaved by endothelin converting enzymes

to form endothelin 1

Bradykinin Peptide mediator that acts on endothelial cell receptors to

promote relaxation of adjacent vascular smooth muscle cells

B-type natriuretic peptide Peptide hormone that acts on natriuretic peptide receptors on

vascular smooth muscle cells to promote vasodilatation and on

renal cells to promote elimination of sodium and water

Corin Enzyme that splits atrial natriuretic peptide precursor proteins to

the active hormone and amino terminal segment

C-type natriuretic peptide Peptide hormone that acts intracellularly or locally on natriuretic

receptors on vascular smooth muscle cells to promote vasodilatation

Cyclic adenosine The active intracellular second messenger that activates protein

monophosphate kinase A

Cyclic guanosine The intracellular second messenger that activates protein kinase G

monophosphate

Diacylglycerol The intracellular second messenger that activates protein kinase C

Endothelin 1 Endothelium-derived peptide that acts on endothelin receptors

to cause potent vasoconstriction

Furin Enzyme that splits B-type natriuretic peptide precursor proteins to

the active hormone and amino terminal segment

Inositol triphosphate Intracellular second messenger that activates inositol

triphosphate-gated ion channels causing vasoconstriction

Kallidin A peptide member of the kinin family, acts on receptors on endothelial

cells to promote relaxation of adjacent vascular smooth muscle cells

Nitric oxide A gas produced by endothelial cells under certain conditions, diffuses

to adjacent vascular smooth muscle cells and promotes vasodilatation

(continues)

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inhibition of the cardiac accelerator andvasoconstrictor centers and stimulation of thevagal parasympathetic center cause negativechronotropism and inotropism and decrease

arterial pressure. Conversely, when arterialblood pressure decreases, the baroreceptor firingrate also decreases. The decreased firing rate istransmitted to the nucleus tractus solitarius.Subsequent signals then stimulate the vasocon-strictor and cardiac accelerator regions of thebrain and simultaneously inhibit the vagalparasympathetic center.12 The net results arevasoconstriction and positive chronotropism,inotropism, and lusitropism, all of which acutelyrestore arterial blood pressure.

Cardiopulmonary baroreceptors, or low-pressure baroreceptors, exist within the wallsof the atria, ventricles, and pulmonary veins.Like other baroreceptors, low-pressure barore-ceptors are nerve endings that are sensitive topressure. Cardiopulmonary baroreceptors alsotransmit signals to the nucleus tractus solitariusvia the vagus nerve.15 The key difference in low-pressure baroreceptors is that they are sensitiveto filling (or venous) pressures instead of arte-rial pressure. Thus, activation of low-pressurebaroreceptors is anticipated in response to achange of blood volume or blood return to theheart as opposed to a change in mean arterialpressure.

Table 3: Major Mediators of Neurohormonal Activation in Heart Failure (Continued)

Mediator Predominant Effect

Norepinephrine Neurotransmitter of most sympathetic postganglionic neurons, acts

on adrenergic receptors causing positive chronotropism,

inotropism, lusitropism, and vasoconstriction

Phosphatidylinositol Membrane phospholipid hydrolyzed by phospholipase C to form

biphosphate intracellular second messengers inositol triphosphate and diacylglycerol

Phospholamban Membrane protein that inhibits the rate of calcium removal by

sarcoplasmic reticulum adenosine triphosphatase (ATPase)

Protein kinase A Enzyme activated by cyclic adenosine monophosphate—modulates

intracellular targets by phosphorylation, leading to positive

chronotropism, inotropism, and lusitropism

Protein kinase C Enzyme activated by diacylglycerol and calcium—modulates

intracellular targets by phosphorylation, leading to vasoconstriction

Protein kinase G Enzyme activated by cyclic guanosine monophosphate—modulates

intracellular targets by phosphorylation, leading to vasodilatation

Renin Enzyme secreted by renal juxtaglomerular cells—cleaves

circulating angiotensinogen to form angiotensin I

Sarcoplasmic reticulum Sarcoplasmic reticulum membrane-bound transport protein that

calcium ATPase removes calcium from the intracellular space during diastole

to augment lusitropism, also known as sarcoplasmic

reticulum calcium adenosine triphosphatase

Figure 1: Sequence of cardiovascular autonomic

nervous system regulation.

Abbreviations: �, change; NTS, nucleus tractus

solitarius of the medulla oblongata; PNS,

parasympathetic nervous system; SNS,

sympathetic nervous system.

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In combination, cardiopulmonary and high-pressure baroreceptors control minute-to-minute changes in cardiovascular homeostasisby responding to changes in intravascular fluidvolume and pressure.

Chemoreceptor FunctionSeveral chemoreceptors and associatedchemoreflexes exist in the human body.Chemoreceptors are nerve endings that termi-nate in highly vascularized areas and are sensitive to changes in plasma chemical con-centration.12 Not surprisingly, the predominanteffects of chemoreceptors that respond tochanges in plasma oxygen or carbon dioxidelevels are mediated through changes in respira-tory rate.11 However, in conditions of low oxygen delivery to tissue, such as in HF,chemoreceptor activation may play a role inmodulation of the cardiovascular system.

Central chemoreceptors, located in the brainstem, primarily respond to hypercapnia.11,16

Activation of these chemoreceptors is part ofthe central nervous system ischemic responsethat gives rise to increased sympathetic activity,including increased respiratory rate, heart rate,and blood pressure.12,16 Peripheral chemorecep-tors, located in the carotid bodies of the inter-nal carotid arteries and the aortic arch,primarily respond to hypoxia.11,17 Similar tobaroreceptors, carotid sinus chemoreceptorstransmit signals to the medulla by way of Hering’s nerve and the glossopharyngeal nerve,and aortic arch chemoreceptors transmitimpulses via the vagi.12 Peripheral chemorecep-tors are highly vascularized and thus are able todetect minute changes in plasma solutes such asoxygen, carbon dioxide, lactic acid, andsodium.12 The predominant effect of chemore-ceptor response to low plasma oxygen or highplasma carbon dioxide is to stimulate anincrease in respiratory rate. Acting via thenucleus tractus solitarius and medullary auto-nomic regions, chemoreceptor stimulation byhypoxia or hypercapnia increases sympatheticoutflow to heart and vasculature, resulting inboth tachycardia and vasoconstriction.11,15

NorepinephrineNorepinephrine (NE) is a catecholamine thatis synthesized and stored in vesicles withinsympathetic nervous system fiber terminals.5

Norepinephrine, among other catecholamines,is also synthesized and released from the adre-nal medulla.18 In neurons, NE synthesis occurs

within the axoplasm of terminal nerve endings. The amino acid tyrosine is hydroxy-lated (addition of a hydroxyl group) to formdihydroxyphenylalanine, which is decarboxy-lated (removal of a carboxyl group) to formdopamine.19 Once transported to presynapticvesicles, further hydroxylation results in NErelease.12 Norepinephrine is hydrophilic; thus,it works by binding to plasma membranereceptors and activating intracellular secondmessengers. When NE is released from thenerve endings, it binds with one of severaladrenergic receptors on the postsynaptic mem-brane and stimulates a sequence of chemicalevents. Much of the NE is taken up into thenerve terminal by a reuptake system, but somemay spill into the circulation. High levels ofplasma NE have been detected in patients withHF20 and are an independent predictor of mor-tality in this population.21

Cardiovascular Adrenergic Receptorsand Physiologic Consequences of Activation�-Adrenergic ReceptorsIn the heart, �1-adrenergic receptors predomi-nate and are coupled with a stimulatory Gprotein.22 When NE binds with a �1-adrenergicreceptor (Figure 2), the � subunit of the stimu-latory G protein dissociates and increases theactivity of the enzyme adenylyl cyclase. Adeny-lyl cyclase generates cyclic adenosine mono-phosphate from adenosine triphosphate (ATP).23

Cyclic adenosine monophosphate acts withincells as the second messenger of NE.7 In sinoa-trial node cells, cyclic adenosine monophos-phate interacts directly with sodium ionchannels known as funny sodium channels(Naf, or if channels).9 Modulation of funnysodium channels by cyclic adenosine mono-phosphate increases sodium influx during dias-tolic depolarization, thus increasing heart rate(positive chronotropic mechanism). Cyclicadenosine monophosphate also activates cyclicadenosine monophosphate-dependent proteinkinase A (PKA). Protein kinase A acts on intra-cellular protein targets by adding a high-energyphosphate, a process called phosphorylation.9

Phosphorylation of target proteins modulatestheir activity. In pacemaker cells, PKA phos-phorylates T-type calcium ion channels,increasing calcium influx during diastolicdepolarization (positive chronotropic mecha-nism).6 In contractile cells, PKA phosphorylatesL-type calcium ion channels, increasing the

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amount of intracellular calcium available forcross-bridge formation during systole, leadingto a greater force of contraction (positiveinotropic mechanism).9

When activated, PKA also phosphorylates aprotein called phospholamban on the mem-brane of the sarcoplasmic reticulum.7 Undernormal conditions, phospholamban partiallyinhibits the actions of an enzyme called sar-coplasmic reticulum calcium adenosine triphos-phatase (ATPase) (also known as SERCA).Sarcoplasmic reticulum calcium ATPase facili-tates the reuptake of calcium into the sarcoplas-mic reticulum for storage during diastole.Phosphorylation of phospholamban gives riseto enhanced SERCA activity, increasing the rateof calcium removal from the intracellularspace.7 This results in an enhanced rate of con-tractile protein and chamber relaxation,enhancing ventricular filling (lusitropic mecha-nism).24 �1-Adrenergic receptors are also locatedin the juxtaglomerular cells of the kidneys andincrease renin release when stimulated.25 The

consequences of increased renin release aredescribed in detail in the RAAS section.

Cardiovascular �2-adrenergic receptors arenormally coupled with a stimulatory G proteinbut may also be coupled with an inhibitory Gprotein22 (Figure 3). If the � subunit of stimula-tory G protein dissociates, the result is positivechronotropism, inotropism, and lusitropism. Ifthe � subunit of the inhibitory G protein disso-ciates, adenylyl cyclase is inhibited and intracel-lular pathways that lead to chamber remodelingare activated.22 Stimulation of �2-adrenergicreceptor may either promote positive inotro-pism, chronotropism, lusitropism, and prolifer-ative effects or exert mixed proliferative andcardioprotective effects.23 That is, stimulatory Gprotein activity also causes cardiomyocyteapoptosis.23,26 In contrast, inhibitory G proteinactivity initiates cell survival signaling andinhibits apoptosis.23,26

�3-Adrenergic receptors are less welldescribed but have been found in the heart.27,28

It is generally accepted that activation of

Figure 2: �1-Adrenergic receptor stimulation—contractile and pacemaker cell. (1) Positive inotropism—

increased intracellular calcium available for cross-bridge formation and contractile force; (2) positive

chronotropism—increased rate of sodium and calcium entry during diastolic depolarization increases heart

rate; and (3) positive lusitropism—enhanced rate of calcium removal from the cytoplasm into the

sarcoplasmic reticulum speeds the rate of cross-bridge relaxation.

Abbreviations: NE, norepinephrine; B1AR—�1-adrenergic receptor; Gs, stimulatory G protein; AC, adenylyl

cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A;

CaL

2�, L-type calcium channel; Ca2�, calcium, PL, phospholamban; SERCA sarcoplasmic reticulum calcium

adenosine triphosphatase; CaT

2�, T-type calcium channel; Na�, sodium, Naf

�, funny sodium channel.

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�3-adrenergic receptors results in negativeinotropism.26–28 When stimulated, �3-adrenergicreceptors inhibit the actions of adenylylcyclase by coupling with an inhibitory G pro-tein and activate nitric oxide synthase.22

Inducible nitric oxide synthase and subsequentnitric oxide production within cardiac cellsmodulate inotropism by influencing calciuminflux via L-type calcium channels.29,30 Nitricoxide also alters ryanodine receptor activity.29

Ryanodine receptors exist within the cyto-plasm of cardiac cells and modulate the releaseof calcium that is stored in the sarcoplasmicreticulum. Ryanodine is one of the cellularproteins that is phosphorylated by PKA inresponse to �-adrenergic stimulation.29 Inresponse to sympathetic nervous system stim-ulation, ryanodine phosphorylation con-tributes to positive inotropism.31 By bluntingthe effect of sympathetic nervous systemstimulation, nitric oxide produced within thecardiac cell limits both the positive inotropiceffects of ryanodine phosphorylation and thepositive lusitropic effects of phospholamban phosphorylation.29,30

In summary, NE can exert different effectson cardiac cells depending on the type of �-adrenergic receptor with which it binds andthe type of G protein with which the receptoris coupled. Alterations in � receptors and Gproteins in the context of HF and chronicmanagement with �-blocking drugs bothmake the short- and long-term effects of sym-pathetic stimulation in the failing heart diffi-

cult to predict. Sympathetic stimulation actingon �-adrenergic receptors may serve either acardioprotective or a deleterious function inthe failing heart.

�-Adrenergic Receptors�1-Adrenergic receptors have widespread dis-tribution on vascular smooth muscle cells andin other tissues, including the heart.26 Whenstimulated with NE, �1-adrenergic receptorspromote contraction of these tissues by increas-ing intracellular calcium. These receptors arecoupled with a third subtype of G protein: Gq

22

(Figure 4). Phospholipase C is activated by Gq,which in turn hydrolyzes a cell membranephospholipid called phosphatidylinositolbiphosphate.9 Phosphatidylinositol biphos-phate is broken down into 2 intracellular sec-ond messengers: inositol triphosphate anddiacylglycerol.32 Inositol triphosphate activatesinositol triphosphate-gated calcium ionchannels,9 increasing intracellular calcium viarelease from endoplasmic reticulum stores.7,32

Diacylglycerol activates protein kinase C,32

resulting in phosphorylation of many intracel-lular proteins.7 Protein kinase C is thought todirectly phosphorylate ion channels thatcontribute to increased calcium concentrationand subsequently slightly increases contrac-tile force.7,9 In addition, diacylglycerol isthought to be a modulator of the proliferativeresponse to HF.9

In response to chronic activation, �1-adrenergic receptors uncouple from stimulatory

Figure 3: B2AR stimulation—B2ARs’ couple with either stimulatory or inhibitory G proteins and can

catalyze either stimulation or inhibition of adenylyl cyclase. In the event of Gi coupling, adenylyl cyclase is

inhibited and intracellular pathways that cause cell proliferation are activated leading to remodeling and cell

survival signals. In the event of Gs coupling, adenylyl cyclase is stimulated to generate cAMP from ATP.

Abbreviations: NE, norepinephrine; B2AR, �2-adrenergic receptor; Gi, inhibitory G protein; Gs, stimulatory G

protein; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate.

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G proteins, a process brought about by phos-phorylation of receptor subunits by �-adrenergicreceptor kinase.28 �-adrenergic receptor kinaseonly phosphorylates �1-adrenergic receptorsthat are occupied by receptor agonists (likeNE), preventing the receptor from activatingG proteins and facilitating the binding of �-arrestins.26 �-Arrestins are proteins thatuncouple receptors from G proteins and, inthis context, completely inactivate �-adrenergic receptors.9,26 In HF, �2-adrenergicreceptors are thought to couple more withinhibitory G proteins than stimulatory G pro-teins; thus, adenylyl cyclase is frequentlyinhibited.23 �3-adrenergic receptor-mediatednitric oxide production may also attenuate thepositive inotropic effects of the sympatheticnervous system.27,30

There are detrimental effects of chronicsympathetic nervous system stimulation inHF, including altered adrenergic receptorfunction. The detrimental effects of chronicsympathetic nervous system activation mustalso be considered in the context of activa-tion of multiple neurohormonal systems, pre-dominantly RAAS.

Part II: The RAASThe RAAS is essential to the maintenance offluid and sodium balance and hemodynamicstability.33,34 Moreover, RAAS activation playsan important role in both adaptive and mal-adaptive mechanisms in response to HF.35 Boththe classic model of RAAS and newly identi-fied components of this complex system arepresented herein. Elements of the RAAS alsoexist in several tissue types. Several tissues,including heart, brain, vasculature, adiposetissue, and adrenal glands have all been showncapable of endogenous expression of RAAScomponents.25,34 Juxtaglomerular cells of therenal afferent arterioles are the main source ofcirculating renin, and hepatocytes are the mainsource of circulating angiotensinogen, but var-ious tissue RAASs may contribute to the localproduction of RAAS mediators.

ReninRenin is an enzyme produced and secreted fromthe juxtaglomerular cells of the renal afferentarterioles.25,34 Within the endoplasmic reticulumof the juxtaglomerular cells, a 401-amino acidprecursor protein (preprorenin) is cleaved to

Figure 4: �1AR activation in vascular smooth muscle. On occupation of the �1AR with NE, Gq dissociates

from the G-protein complex and activates PLC. PLC hydrolyzes PIP2 into IP3 and DAG. IP3 activates IP3-

gated calcium channels on the sarcoplasmic reticulum membrane, triggering calcium release into the

cytoplasm. DAG stimulates PKC, which phosphorylates cation (most likely calcium) channels contributing

to increased intracellular calcium. DAG also causes proliferative effects.

Abbreviations: NE, norepinephrine; �1AR, �-1 adrenergic receptor; Gq, type q G protein; PLC,

phospholipase C; PIP2, phosphatidylinositol biphosphate; IP3, inositol triphosphate; DAG, diacylglycerol;

Ca2�, calcium; PKC, protein kinase C.

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form prorenin.34 Prorenin is then cleaved by atrypsin-like activating enzyme to form renin.34

Renin is most identifiable as the enzyme thatcleaves angiotensinogen. Angiotensinogen is aprotein synthesized and secreted by the liverinto the circulation where it is cleaved to formangiotensin I34 (Figure 5). Angiotensin I is thenhydrolyzed by angiotensin-converting enzyme(found predominantly in pulmonary capillaries)to form biologically active angiotensin II (ANGII).34 Active angiotensin II has several knownbiologic effects, including vasoconstriction and sodium and water retention.36 Activeangiotensin II also has profibrotic and proin-flammatory effects33 that contribute to unto-ward cardiac chamber remodeling.

Mechanisms of RAAS ActivationRenin secretion is controlled by several intrinsicintrarenal mechanisms, in addition to controlby the sympathetic nervous system. In the distalthick ascending limb of the loop of Henle,

macula densa cells are both electrically andchemically coupled with juxtaglomerular cellsof the afferent arterioles by mesangial cells.37

This coupling promotes an inverse relationshipbetween renal tubular sodium chloride concen-tration and plasma renin concentration.25

Decreased tubular lumen sodium chloride con-centration facilitates 2 events leading to reninsecretion from juxtaglomerular cells. First,decreased sodium chloride uptake from thelumen into the macula densa cells via thesodium-potassium-2 chloride cotransporterincreases calcium within macula densa cells.38,39

Increased intracellular calcium activates phos-pholipase A2 and leads to production ofprostaglandins from arachidonic acid.38,39

Prostaglandin E2 is a known stimulus for reninrelease from the adjacent juxtaglomerularcells.39 Second, decreased tubular fluid sodiumchloride concentration results in decreased ionpumping and ATP consumption, thus reducingthe breakdown of ATP to adenosine in macula

Figure 5: Renin-angiotensin-aldosterone system. Abbreviations: ACE, angiotensin-converting enzyme; AVP,

arginine vasopressin; MAP, mean arterial pressure; NE, norepinephrine; Na, sodium.

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densa cells.39,40 Adenosine is a known inhibitorof renin release from the juxtaglomerularcells.39,40 Thus, renin release from juxtaglomeru-lar cells is favored by either increased pro-staglandin E2 or decreased adenosine productionby macula densa cells.

A pressure-sensitive mechanism of reninrelease also exists.41,42 In fact, the pressure-sensitive and sodium chloride load mecha-nisms combined make up what is calledtubuloglomerular feedback, which plays animportant physiologic and pathophysiologicrole in regulating renal hemodynamics.38,40,43

Stretch of the juxtaglomerular cells inhibitsrenin release and may also interfere withprorenin transcription.41 Using data from ananimal model, researchers found that stretch-ing macula densa cells led to increased adeno-sine production.42 Adenosine can diffuse frommacula densa cells to vascular smooth musclecells in the afferent arteriole wall and causevasoconstriction, inhibiting renin secretionfrom juxtaglomerular cells.42

Sympathetic nervous system activation alsostimulates renin release. This response is medi-ated by activation of �1-adrenergic receptorson the cell surface of juxtaglomerular cells byNE.25 Cyclic adenosine monophosphate acts asthe intracellular second messenger, directlystimulating renin release from secretory granules.25 In HF, decreased filtered sodiumchloride load, decreased renal arterial pres-sure, and elevated levels of circulating neuro-hormones (eg, NE), all contribute to increasedrenin release. As renin is secreted into the cir-culation (and possibly in selected tissues), itpromotes increased levels of angiotensin I,ultimately increasing circulating ANG II.

Angiotensin II Receptors and the Effects of ActivationTwo ANG II receptor subtypes have been iden-tified: AT1 and AT2.

44,45 The majority of biologiceffects of ANG II expression are mediated viaAT1 receptors.45,46 AT1 receptors are found onvascular smooth muscle cells and in the heart.AT1 receptors are predominantly Gq-coupledand when occupied activate phospholipase C.45

Phospholipase C activation leads to the hydrol-ysis of phosphatidylinositol biphosphate, stim-ulation of inositol triphosphate-mediatedcalcium release from the endoplasmic reticu-lum, and activation of protein kinase C by dia-cylglycerol.45 The result is increased intracellularcalcium, increased contractile force, and subse-

quent vasoconstriction of vascular smoothmuscle. In response to chronic activation, AT1

receptors activate intracellular pathways thatlead to proliferative cellular remodeling.9 InHF, not only does ANG II stimulate undesiredvasoconstriction but also cellular structuralchanges that further impair contractile func-tion, including hypertrophy and fibrosis.

Vascular and tubular AT1-receptor activationincreases renal sodium and water retention andthereby increases blood volume.34 First, AT1-receptor activation leads to calcium-mediatedvasoconstriction of both afferent and efferentrenal arterioles, which decreases renal bloodflow and thereby sodium and volume deliveryto the glomerulus.34 Second, vasoconstrictionalso limits medullary blood flow, favoring pas-sive sodium and water reabsorption in the loopof Henle.34 In the proximal tubule, AT1-receptoractivation enhances lumenal sodium-hydrogenexchange and sodium-bicarbonate cotransportand activates sodium-potassium ATPase on thebasolateral membrane.34 In the distal tubule,AT1-receptor activation enhances sodium-hydrogen exchange and epithelial sodium chan-nel activity.34 All renal actions of AT1-receptoractivation thus promote sodium reabsorptionand limit sodium elimination, favoring anincrease in blood volume.

AT1 receptors are found in several brainregions critical for fluid, electrolyte, and vol-ume homeostasis. Neurons projecting to thesupraoptic and paraventricular nuclei andanterior pituitary can stimulate arginine vaso-pressin secretion from the posterior pituitary.45

Neurons projecting to the median opticnucleus45 and subfornical organ47 can alsostimulate thirst. Increased calcium currentsdue to AT1-receptor activation mediate theneuronal effects of ANG II.

In the cortex of the adrenal gland, zonaglomerulosa cells respond to AT1-receptor acti-vation with aldosterone secretion.48 In fact, inpersons with chronically activated RAAS,zona glomerulosa cell hypertrophy is oftencaused by chronic ANG II stimulation.49 Byactivating Gq proteins, AT1-receptor activa-tion leads to increased intracellular calcium.Increased intracellular calcium stimulatesaldosterone secretion. Aldosterone binds withrenal mineralocorticoid receptors in principalcells of late distal tubule and promotes sodium(and secondarily water) retention.48,49

AT2 receptors are different from AT1 recep-tors in several ways. First, AT2 receptors are

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ubiquitous only at birth, but they are alsofound in the heart of older humans in diseasestates like HF.34,45 Second, activation of AT2

receptors is thought to be initially cardiopro-tective.34,46 Although the subject of ongoinginvestigation, AT2-receptor activation ishypothesized to involve activation of amembrane potassium channel (delayed Krectifier),34 and inactivation of T-type calciumchannels.44,45 Together, these cause relaxationof vascular smooth muscle and decreasedresponsiveness to vasoconstrictive substancessuch as NE. In the heart, AT2-receptor activa-tion may counteract certain AT1-receptor-mediated effects, but it has also been linkedwith cardiac chamber hypertrophy, fibrosis,and apoptosis.50

In summary, although ANG II-receptoractivation helps restore arterial pressure byvasoconstriction and water and sodium reten-tion in the acute phase of HF, chronic stimula-tion of RAAS further perpetuates HF bycausing increased blood volume and periph-

eral vascular resistance and directly triggeringcardiac chamber remodeling.

Modern Model of RAASDecades of research have led to the discoveryof several new aspects of RAAS, which isoften simplified for clarity (Figure 6). First,the peptide kallikrein can cleave prorenin torenin and cleave angiotensinogen directly toANG II.34 Second, other substances, includingheart or other tissue chymase enzymes, cancleave angiotensin I to form ANG II.34

Third, angiotensin-converting enzyme II con-verts angiotensin I to a metabolite, AT(1–7), withvasoactive properties and a unique receptor.33,34

The conversion of angiotensin I to AT(1–7) mayalso be mediated by neutral endopeptidases.Activation of the AT(1–7) receptor by this meta-bolite leads to vasodilatation,33,34,51 counteract-ing the effects of ANG II. Fourth, aldosteroneis hypothesized to augment conversion ofangiotensin I to ANG II in a positive feedbackmechanism.8 Finally, angiotensin-converting

Figure 6: RAAS Activation: Simple and modern models. (a) Simple RAAS model. (b) Complex RAAS model.

Abbreviations: RAAS, renin-angiotensin-aldosterone system; ACE, angiotensin-converting enzyme; ACE II,

angiotensin-converting enzyme II; NEP, neutral endopeptidases; ANG1–7, angiotensin metabolite 1–7; AT1R,

angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; AVP, arginine vasopressin; B1, kinin

receptor type 1; B2, kinin receptor type 2.

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enzyme also serves to cleave another activepeptide bradykinin to its metabolites.Bradykinin, as described in detail in the subse-quent text, also has vasodilatory and cardio-protective properties.

Part III: The Kallikrein-Kininogen-Kinin SystemThe kallikrein-kininogen-kinin system isimportant in the study of HF because of thecrossover between the kallikrein-kininogen-kinin system and RAAS and the cardioprotec-tive effects of the biologically active kinins.52–54

Bradykinin and kallidin are formed by aninteraction between precursor molecules.55

Mechanisms of Kallikrein-Kininogen-Kinin System ActivationThe kinin system involves several precursorproteins that are cleaved by proteases to formactive mediators, similar to the clotting andangiotensin cascades. Two pathways areincluded in this system (Figure 7). First, tissueprekallikrein is activated by plasmin or plasmakallikrein to form active tissue kallikrein.54

Active tissue kallikrein releases the vasoactivepeptide kallidin from low-molecular-weightkininogen.52 As with angiotensinogen, low-molecular-weight kininogen is synthesized byhepatocytes and secreted into the circulation.52,54

Kallidin is further broken down by anaminopeptidase to form bradykinin.52 Second,hepatocytes also produce plasma prekallikrein,which is converted to active plasma kallikrein

by activated Hageman factor (coagulation fac-tor XIIa).52 Active plasma kallikrein then acts torelease bradykinin from high-molecular-weightkininogen, a substance also produced primarilyin the liver.52,54 Bradykinin is degraded into inac-tive metabolites by enzymes known as kininasesor a neutral endopeptidases.36,53 Most notably,kininase II is the same enzyme as angiotensin-converting enzyme, which is responsible for theconversion of angiotensin I to ANG II. That is,the same enzyme breaks down bradykinin toactive and inactive metabolites and convertsangiotensin I to ANG II.52–54

Kallikrein-Kininogen-Kinin SystemReceptors and Effects of ActivationTwo kinin receptors have been identified inhumans: kinin receptor type 1 (B1) and kininreceptor type 2 (B2).

52–55 The B1-kinin receptor isnormally not expressed in healthy human tis-sue but is thought to become significantlyactive in inflammatory or injury-responseconditions.54 In particular, expression of B1-kinin receptors in coronary vascular endothelialcells is increased in patients with HF.56 B1-kininreceptors have a high affinity for bradykininmetabolites but not bradykinin itself.53 Whenoccupied, B1-kinin receptors stimulate Gq-medi-ated activation of phospholipase C.52,54

Phospholipase C hydrolyzes phosphatidylinosi-tol biphosphate, which is broken down into inositol triphosphate and diacylglycerol(Figure 8). Inositol triphosphate increasesintracellular calcium by activating inositol

Figure 7: Kallikrein-kininogen-kinin system. Abbreviations: ACE, angiotensin-converting enzyme; NEP,

neutral endopeptidase; LMW, low molecular weight; HMW, high molecular weight; B1 receptor, kinin

receptor type 1; B2 receptor, kinin receptor type 2; Factor XIIa, Hageman coagulation factor.

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triphosphate-gated calcium ion channels on theendoplasmic reticulum.57

Diacylglycerol activates protein kinase C,32

resulting in the phosphorylation of many intra-cellular targets that also increase intracellular cal-cium concentrations. Increased intracellularcalcium in endothelial cells promotes the produc-tion of nitric oxide and subsequently increasescyclic guanosine monophosphate production inadjacent vascular smooth muscle cells.53,54,58 Ele-vated levels of cyclic guanosine monophosphatein vascular smooth muscle cells promote vasodi-latation. B1-kinin receptor stimulation alsoactivates phospholipase A2, liberating arachi-donic acid and its metabolites from the cellmembrane.54,57 Important by-products of arachi-donic acid are prostaglandins, specifically prost-aglandin I2 and E2, which may also play a role inadjacent vascular smooth muscle cell relax-ation.53,54 Furthermore, the B1-kinin receptors arealso coupled with inhibitory G proteins57 and caninhibit the actions of adenylyl cyclase.

Although the intracellular signaling of B1-kinin receptors and B2-kinin receptors is simi-

lar, a few key differences are important tonote. First, unlike B1-kinin receptors, B2-kininreceptors are constitutively expressed inhealthy individuals and are downregulated inpatients with HF.59 Second, the B2-kinin recep-tors have a higher affinity for bradykinin andkallidin,57,58 not bradykinin metabolites. Third,activation of B1-kinin receptors results in a sus-tained increase in intracellular calcium, whereactivation of B2-kinin receptors results in atransient increase in intracellular calcium.54,57

Fourth, B2-kinin receptors suffer significantdesensitization, where B1-kinin receptors donot.54,59 Finally, B2-kinin receptors may directlyactivate membrane calcium channels andthereby increase intracellular calcium inendothelial cells.54

Because the kinins and their metabolites arelargely viewed as endogenous vasodilators,their role in HF pathogenesis is gaining inter-est. Under conditions of angiotensin-convert-ing enzyme inhibition and partial blockade ofAT receptors, the potential cardioprotectiverole of bradykinin in HF may be manifested.

Figure 8: B2-kinin receptor-mediated vasodilatation. In endothelial cells, B2-KR activation increases

intracellular calcium, which promotes eNOS and NO production. PKC also activates PLA2, which releases

AA from membrane lipids—the initial step leading to PGE2 and PGI2 synthesis. NO, PGE2, and PGI2

increase cGMP in adjacent vascular smooth muscle cells, thereby promoting vasodilatation.

Abbreviations: BK, bradykinin; B2-KR, type 2 kinin receptor; Gq, type q G protein; Gi, inhibitory G protein;

AC, adenylyl cyclase; PLC, phospholipase C; PIP2, phosphatidylinositol biphosphate; IP3, inositol

triphosphate; DAG, diacylglycerol; Ca2�, calcium; ER, endoplasmic reticulum; eNOS, nitric oxide synthase;

NO, nitric oxide; cGMP, cyclic guanosine monophosphate; PLA2, phospholipase A2; AA, arachidonic acid;

PGE2, prostaglandin E2; PGI2, prostaglandin I2 (prostacyclin); PKC, protein kinase C.

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Part IV: Natriuretic Peptide SystemIn 1964, first evidence emerged that the heartis an endocrine organ, producing and express-ing endogenous hormones.60 Since that time, 2natriuretic hormones have been identified ashaving a role in HF: atrial natriuretic peptide(ANP) and B-type natriuretic peptide (BNP).These natriuretic peptides play an importantregulatory role in volume homeostasis,61 hav-ing several beneficial and cardioprotectiveeffects62 including natriuresis, vasodilatation,and modulation of both the sympathetic nerv-ous system and RAAS.62–64 C-type natriureticpeptide (CNP), a peptide produced byendothelial cells,64 has also been identified inhumans.61 All natriuretic peptides are continu-ously secreted but are found in elevated levelsin HF cases.

Atrial Natriuretic PeptideAtrial natriuretic peptide is a biologicallyactive, 28-amino acid hormone that is prima-rily synthesized by atrial myocytes.64 Atrialnatriuretic peptide is synthesized, stored, andsecreted to a lesser extent in healthy ventricularmyocytes,61 although ventricular ANP synthesisincreases in HF.64 It is stored as part of the 126-amino acid precursor protein proANP. Whensecreted from granules of atrial cells, proANPis split by the enzyme corin into the amino ter-minal portion, Nt-proANP1–98, and the activehormone ANP99–126.

64 Corin is an enzyme that isproduced in both the atrial and ventricularmyocytes; however, levels are much greater inthe atria.63 Although they are secreted in equalamounts, the active hormone ANP99–126 has amuch shorter half-life than Nt-proANP1–98: 1 to5 minutes and 40 to 50 minutes, respec-tively.61,64 This is due to a binding of the activehormone to natriuretic peptide receptors andrapid enzymatic degradation by a neutralendopeptidase.63–65

B-Type Natriuretic PeptideB-type natriuretic peptide is a biologicallyactive, 32-amino acid hormone that is synthe-sized in both atrial and ventricular myocytes.In fact, in nonfailing hearts more BNP issecreted from the atria than from the ventri-cles66 and more ANP is secreted than BNP.64 Infailing hearts, however, the expression andsecretion of both BNP and ANP areincreased.64,66,67 ProBNP is a 108-amino acidprohormone that is split by the enzyme furin

into the amino terminal fragment (Nt-proBNP1–76) and the active peptide BNP77–108.

64

The enzyme corin may also play a role in theprocessing of proBNP.63,65,66 In the atria,BNP77–108 may be stored in the same secretorygranules with ANP99–126.

66 BNP77–108 has ashorter half-life that its amino terminal frag-ment Nt-proBNP1–76, 22 minutes and 70 min-utes, respectively.64 BNP77–108 has a longerhalf-life than ANP99–126 because of a higherreceptor affinity for the latter.64

C-Type Natriuretic PeptideC-type natriuretic peptide is synthesized as a103-amino acid precursor protein: proCNP.ProCNP is cleaved to form an amino terminalfragment and 1 of 2 biologically active pep-tides: CNP51–103 or CNP82–103.

63,65,68 The aminoterminal fragments of proCNP (Nt-proCNP1–81

or Nt-proCNP1–50) have longer half-lives, justlike the other natriuretic peptides.63,68 C-typenatriuretic peptide is predominantly anendothelial product and is thought to havemore local (paracrine) or intracellular(autocrine) effects than endocrine function.64,68

C-type natriuretic peptide is also produced infailing human hearts.69

Mechanisms of Natriuretic Peptide ExpressionBoth ANP and BNP are continuously secretedfrom the heart, but expression and secretionare increased in response to various stimuli.61

Constitutive secretion is most likely caused bypassive diffusion of the natriuretic peptidesfrom the specific atrial granules that storethem.63,65 Regulated secretion involves releaseof the natriuretic peptides from storage gran-ules in response to an agonist,63 several ofwhich have been identified. Agonists includeepinephrine, NE, acetylcholine, arginine vaso-pressin, endothelin 1, ANG II, and numerousinflammatory cytokines.61,64,65 Natriuretic ago-nists not only modulate the hemodynamicstimuli for peptide expression but also directlystimulate their release.64

The predominant mechanism for ANP andBNP secretion is wall stretch,61,63–65 activatingwhat is known as stretch-secretion cou-pling.70,71 In response to stretch, natriureticpeptides are immediately secreted into the cir-culation.64,70 Storage granules contain moreANP than BNP, so ANP levels show a greaterinitial increase than BNP in response to acutestretch.64 Wall stretch also leads to depletion of

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stored natriuretic peptides.65 In chronic wallstretching due to intravascular fluid volumeoverload, synthesis of natriuretic peptides isenhanced to replace that which was secreted.Induction of natriuretic peptide synthesis andstorage gives rise to elevated levels that areseen in patients with HF. Because circulatinglevels of ANP and BNP reflect the severity ofHF, serum levels of BNP77–108 and Nt-proBNP1–76 are used as diagnostic and prog-nostic indicators for patients with HF72–75

Elevated levels of active BNP and amino-terminal portions in HF reflect greater synthe-sis and secretion, less clearance by enzymaticdegradation, and less affinity for the natri-uretic peptide clearance receptor.64

Natriuretic Peptide Receptors and the Effects of ActivationThree natriuretic peptide receptors have beenidentified: type A, type B, and type C. Both typeA and B receptors are responsible for theknown physiologic and pathophysiologiceffects of this system of protein hormones.61,63,65

Atrial natriuretic peptide and BNP preferen-tially bind to type A receptors, where CNP pref-erentially binds to type B receptors.61,63,65 Bothtype A and B receptors are found in the kidneys,vascular smooth muscle, adrenal glands, theheart, and the brain.61,63,65 Natriuriuretic peptidetype A receptors have greater affinity for ANPthan for BNP and CNP, respectively.76 Natriuri-uretic peptide type B receptors have greateraffinity for CNP than for ANP and BNP, respec-tively.76 Both natriuretic peptide type A and Breceptors are part of the extracellular portion ofthe membrane-bound enzyme particulateguanylyl cyclase.77 When the receptor is occu-pied by a natriuretic peptide, the intracellularportion of guanylyl cyclase is stimulated.77

Guanylyl cyclase generates cyclic guanosinemonophosphate from guanosine triphosphate.As the intracellular second messenger, cyclicguanosine monophosphate then stimulatescyclic guanosine monophosphate-dependentprotein kinase G (PKG) and cyclic guanosinemonophosphate-gated ion channels.63,77

In contrast, natriuretic peptide type C recep-tors are responsible for natriuretic peptideclearance.61,63,65 Type C receptors have beenfound in anatomical areas that receive the great-est cardiac output: the renal, pulmonary andcerebral vasculature, adrenals, and the heartchambers.63,65 Atrial natriuretic peptide bindsmore easily to type C receptors than do CNP

and BNP, respectively.63,65 When occupied by anatriuretic peptide, type C receptors internalize(endocytose), peptide is broken down byhydrolysis, and the receptor returns to themembrane.63,65 Natriuretic peptides can also bedegraded by circulating neutral endopepti-dases.64 These enzymes hydrolyze the natriureticpeptides and are thought to have a greater rolein conditions such as HF, where natriureticpeptide type C receptors may be inundated.63,65

Natriuretic Peptides and Vasodilatation and Cardiomyocyte RelaxationIn vascular smooth muscle and contractileheart cells, the natriuretic peptides act throughincreased levels of cyclic guanosine monophos-phate and the resultant changes in intracellularcalcium.61 Smooth muscle relaxation is a directresult of decreased levels of calcium that arisesby 4 mechanisms (Figure 9). First, calciuminflux into the cell is inhibited by PKG phos-phorylation of L-type calcium channels, andthe cell is hyperpolarized due to activation ofcalcium-dependent potassium channels.63,77

Hyperpolarization makes smooth muscle cellsless prone to stimulation by other vasopressors.Second, calcium efflux is accelerated due toactivation of the sodium/potassium ATPaselocated on the cell membrane and the influenceon sodium/calcium exchange.77 Third, PKGphosphorylation of inositol triphosphate-gatedion channel inhibits the release of calciumstored in the endoplasmic reticulum.77 Fourth,PKG phosphorylation of phospholambanenhances calcium sequestration via the SERCAon the endoplasmic reticulum.77 The net resultof these mechanisms is decreased calcium avail-able for cross-bridge formation and subsequentvasodilatation. Through these same mecha-nisms, the natriuretic peptides counteract theeffects of the sympathetic nervous system andthe effects of ANG II and arginine vasopressinon cardiomyocytes. Particularly in response tochronic HF, natriuretic peptide-induced reduc-tion of intracellular calcium is thought to mod-ulate and ameliorate, at least in part,detrimental cellular and chamber remodelingpromoted by other neurohormones.62

Natriuretic Peptides and Diuresis and NatriuresisA principal target of the natriuretic peptides inthe kidney is the renal arterioles. Vasodilatationof afferent renal arterioles and concomitantvasoconstriction of efferent arterioles lead to

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greater glomerular capillary hydrostatic pres-sure and thereby a greater glomerular filtrationrate.61,78 Collecting duct cells are also a site ofaction of natriuretic peptides.78 In particular,principal cells of the medullary collecting ducthave a high proportion of natriuretic peptidetype A receptors, which facilitate natriuresis inthe following ways.78 First, cyclic guanosinemonophosphate decreases the inward transportof sodium from the lumen of the collecting ductto the medullary interstitium,78 leaving moresodium in the lumen for elimination. Second,cyclic guanosine monophosphate stimulatesPKG, which in turn phosphorylates several proteins, including the same sodium channel onthe lumen membrane (also known as apical

membrane) of the principal cell affected directlyby cyclic guanosine monophosphate, and thesodium potassium ATPase that is located on theperitubular membrane (also known as basolat-eral membrane) of the principal cells.78 Whenreceptors are occupied by natriuretic peptides,this sodium potassium ATPase is inhibited, fur-ther decreasing sodium reabsorption.78 The neteffects of the actions of the natriuretic peptide-stimulated increase in cyclic guanosinemonophosphate are natriuresis and diuresis.

Unlike the majority of the other systemsdescribed, endogenous natriuretic peptides are cardioprotective. Cardioprotection bynatriuretic peptides may be more effective dur-ing simultaneous therapeutic blockade of

Figure 9: Natriuretic peptide type A/B receptor-mediated vasodilatation. Guanylyl cyclase generates

cGMP from GTP. In vascular smooth muscle cells, cGMP stimulates PKG, which phosphorylates several

targets, ultimately leading to vasodilatation due to (1) decreased calcium influx secondary to PKG

phosphorylation of L-type calcium and membrane hyperpolarization due to activation of calcium-dependent

potassium channels; (2) acceleration of membrane sodium/potassium ATPase fuels greater

sodium/calcium exchange and thereby calcium efflux; (3) inhibition of IP3-gated calcium channels,

decreasing intracellular calcium; and (4) PKG phosphorylation of phospholamban accelerates SERCA and

calcium resequestration into the endoplasmic reticulum. All actions favor decreased intracellular calcium,

smooth muscle relaxation, and vasodilatation.

Abbreviations: ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; NPR, natriuretic peptide

receptor; GC, guanylyl cyclase; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate;

PKG, protein kinase G; CaL

2�, L-type calcium channel; KCa

�, calcium-dependent potassium channel; Na/K,

sodium-potassium-ATPase; Na/Ca, sodium-calcium exchange; PL, phospholamban; Ca2�, calcium; SERCA,

sarcoendoplasmic reticulum adenosine triphosphatase; ER, endoplasmic reticulum; IP3-gated Ca2�, inositol

triphosphate-gated calcium channel.

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other systems such as the sympathetic nervoussystem, RAAS, and vasopressinergic system.

Part V: Vasopressinergic SystemArginine vasopressin is a hormone that regu-lates water balance and cardiovascular home-ostasis. Arginine vasopressin is derived from aprecursor hormone synthesized in magnocellu-lar neurons of the paraventricular andsupraoptic nuclei of the hypothalamus.79,80 Pre-provasopressin is composed of 3 proteins—arginine vasopressin, neurophysin II, andcopeptin81—and is transported via the supraop-tic-hypophyseal tract to the axon terminals ofthe magnocellular neurons in the posteriorpituitary.80 The active hormone arginine vaso-pressin is a 9-amino acid protein derived frompreprovasopressin80,81 and is secreted into thecirculation from the posterior lobe of the pitu-itary gland.82

Mechanisms of Arginine Vasopressin ReleaseArginine vasopressin secretion is regulated byboth osmotic and nonosmotic mechanisms.79,80,83

Osmotic secretion is controlled by osmorecep-tors sensing changes in sodium concentration.Osmoreceptors located within the hepaticportal vein detect the impact of dietary intakeon osmolality, transmitting signals via thevagus nerve to the nucleus tractus solitarius,area postrema, and ventrolateral medulla.84

Afferent cells from these areas project to theparaventricular nuclei and supraoptic nucleiand depolarize the magnocellular neurons,resulting in increased arginine vasopressinrelease.79 Other osmoreceptors are foundwithin the hypothalamus itself and project tothe paraventricular and supraoptic nuclei.Arginine vasopressin-secreting mangocellularneurons are also responsive to plasma sodiumlevels.85,86

Nonosmotic arginine vasopressin secretionis particularly important to the study of HF.Baroreceptors in the left atrium, aortic arch,and carotid sinuses transmit afferent impulsesto the nucleus tractus solitarius in response tounderfilling.79 High-pressure baroreceptors(located in the aortic arch and carotids) are pri-marily responsible for initiating nonosmoticarginine vasopressin release.3,80 Low-pressurebaroreceptors also respond to high filling pres-sures; however, this predominantly leads tosympathetic nervous system activation andnatriuretic peptide secretion, not arginine vaso-

pressin release.79 In healthy humans, increasedblood volume that activates low-pressurebaroreceptors is a strong signal for the inhibi-tion of arginine vasopressin secretion.

High levels of arginine vasopressin havebeen detected in patients with HF.82,83 Hypona-tremia, most commonly a menacing sign, isalso a common finding in patients hospitalizedwith HF.87 It is likely that, in HF, nonosmoticarginine vasopressin secretion is the dominantmechanism of hyponatremia.88 In HF, disten-tion of left atrial baroreceptors in response toincreased central blood volume should inhibitarginine vasopressin expression. Furthermore,both central and peripheral chemoreceptorsthat detect decreased levels of sodium shouldalso inhibit arginine vasopressin secretion.That is, in HF there is an apparent override ofcertain nonosmotic and osmotic inhibitory sig-nals to the arginine vasopressin neurons. Theexact mechanisms underlying high levels ofarginine vasopressin in person with HF,however, have not yet been described.89

Vasopressin Receptors and Effect of ActivationThree separate arginine vasopressin receptorshave been identified: V1A, V1B (formally V3),and V2.

90 V1A receptors are found primarily onvascular smooth muscle cells and cardiomy-ocytes.90,91 V1B receptors primarily exist in theanterior pituitary.90,91 Both V1 receptor sub-types are Gq protein coupled.90 (For details, seethe description of �-adrenergic receptor acti-vation and Figure 4.) V1A receptors also modu-late ATP-sensitive potassium channels.80

Adenosine triphosphate-sensitive potassiumchannels typically promote potassium effluxin conditions of hypoperfusion and inhibitcalcium influx, thus inhibiting cells and relax-ing smooth muscle. V1A-receptor activationcloses ATP-sensitive potassium channels,enhancing vascular reactivity to argininevasopressin and other vasoactive substances.80

Therefore, activation of V1A receptors on vas-cular smooth muscle cells leads to vasocon-striction and increased responsiveness tosympathetic nervous system and other systemactivation.

V2 receptors on collecting duct cells of thekidneys mediate the antidiuretic properties ofarginine vasopressin. V2 receptors are coupledwith a stimulatory G protein and, when acti-vated, stimulate adenylyl cyclase. As describedpreviously, adenylyl cyclase generates cyclic

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adenosine monophosphate from ATP. Actingas an intracellular second messenger in renalcollecting duct cells, cyclic adenosinemonophosphate stimulates protein kinase A,which in turn phosphorylates the aquaporin-2molecule.85 When phosphorylated, aquaporin-2 molecules are mobilized to the apical plasmamembrane of the collecting ducts and facilitatewater reabsorption,80,85,90 by forming waterchannels.92 Of particular relevance to thepatient with HF is the fact that activation of V2

receptors does not result in sodium reabsorp-tion as does aldosterone, leading to the reten-tion of water but not sodium, and predisposingto hyponatremia.91

Taken together, the vasocontrictive andwater-retaining effects of arginine vasopressincontribute to HF progression rather than com-pensation.

Part VI: EndothelinEndothelin 1 is a biologically active, 21-aminoacid protein that is synthesized by endothelialcells.93 Although several other endothelinsexist within the body,94 the effects of endothe-lin 1 has been studied to a greater extent in HF.Because of the potent vasoconstrictive proper-ties of endothelin 1, elevated plasma levels ofthis protein in patients with HF are of patho-physiologic significance.

Mechanisms of Endothelin SecretionEndothelin 1 is produced within endothelialcells in response to various stimuli, includingshear stress, hypoxia, and the presence ofother circulating vasoactive hormones suchas ANG II and vasopressin.95 Endothelin 1 isnot constitutively expressed; thus, an alter-ation in endothelial function is required forendothelin 1 secretion. First, the biologicallyinactive 212-amino acid preproendothelin-1is cleaved by a furin-like peptide to formanother biologically inactive 39-amino acidprohormone called big endothelin.95 Bigendothelin is then cleaved by one of severalendothelin converting enzymes to formendothelin 1.96 Recent evidence suggests thatplasma levels of big endothelin and endothe-lin 1 are superior to the natriuretic peptidesin determining survival in patients with HF.97

Although elevated levels of endothelin 1 havebeen described in patients with HF, it remainsunclear if endothelin 1 expression isincreased,94 or if endothelin 1 degradation isdecreased.93

Endothelin Receptors and the Effects of ActivationTwo endothelin receptor subtypes have beenidentified: endothelin 1 type A receptors andendothelin 1 type B receptors.98 Both endothe-lin 1 receptors are Gq-coupled receptors.94,95

(For details, see the description of �-adrenergicreceptors and Figure 4.) Endothelin 1 type Areceptors are found in the vascular smoothmuscle cells of the aorta, kidneys, and on car-diac myocytes.94,95 Activation of vascularsmooth muscle endothelin type A receptorsincreases intracellular calcium and causespotent and sustained vasoconstriction. Interest-ingly, the half-life of endothelin 1 is between 1and 2 minutes, yet the vasoconstrictive effectsof endothelin 1 last up to 60 minutes.94,95 Acti-vation of cardiomyocyte endothelin 1 type Areceptors causes positive chronotropism andinotropism.95 In right atrial myocytes, type Areceptors are also coupled with an inhibitory Gprotein and inhibit adenylyl cyclase, a phenom-enon not found in ventricular myocytes.99

Endothelin 1 type B receptors are foundpredominantly on vascular endothelial cells.95

Endothelin 1 type B receptors on endothelialcells are also coupled with an inhibitory Gprotein and promote nitric oxide sythesis.94,95

Nitric oxide production from activation oftype B receptors on endothelial cells causesvasodilatation by actions on adjacent vascularsmooth muscle cells.95 Type B receptors arealso found on vascular smooth muscle cells,but will promote vasoconstriction by identicalmeans as endothelin 1 type A receptors.95

Thus, the effect of endothelin 1 type B-receptor activation is dependent on anatomiclocation, giving rise to either vasoconstrictionor vasodilatation. Vasoconstriction, particu-larly that which is sustained, further deterio-rates cardiovascular function in HF.

ConclusionIn this article, mechanisms of activation andcellular and organ system effects of severalhormones and mediators in HF have beenreviewed. These included the sympatheticnervous system, RAAS, kallikrein-kininogen-kinin system, natriuretic peptide systems,vasopressin, and endothelin. Individually,these systems are complex, and their interac-tions increase the complexity of pathophysiol-ogy and of care for the patient with HF.Understanding mechanisms of compensatoryneurohormonal system activation and the

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physiologic basis for pharmacologic agentsused in the management of HF, however,serves as an important foundation for under-standing innovations in diagnostic testing anddrug development. Nursing care of patientswith HF will increasingly be influenced by theevolving science emerging from this research.

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